Compared to uninfected subjects, HIV-infected subjects continue to experience an increased incidence of atherosclerotic cardiovascular disease (ASCVD) despite well-controlled viral replication on antiretroviral therapy (ART). Some antiretroviral drugs ? such as abacavir and some protease inhibitors ? have been associated with even higher ASCVD risk. Furthermore, ASCVD risk scores underestimate the ASCVD risk among HIV-infected subjects. This likely suggests that there are unmeasured factors contributing to the increased risk associated with HIV and/or ART. One such potential mechanism is the down-regulation of cholesterol efflux from arterial wall macrophages which as been documented in HIV infection. The impairment of cholesterol efflux capacity (CEC) by HIV may be partially reversed by ART. We have demonstrated that impaired CEC is an ASCVD risk factor in the general population, independent of traditional risk factors including HDL cholesterol (HDL-C) levels. In the proposed analyses we will characterize the clinical relevance of CEC as a cardiovascular biomarker in patients with controlled HIV infection on ART, and determine the impact of various antiretroviral drugs on CEC. We propose to achieve this by measuring CEC in HIV-infected participants of a large AIDS Clinical Trials Group (ACTG) cohort: the Longitudinally Linked Randomized Trials (ALLRT) to establish the association between baseline HDL cholesterol efflux and incident ASCVD among patients with controlled HIV infection on stable ART. We will do so by measuring CEC in ALLRT participants with incident ASCVD and a 5:1 random- sample cohort who remained free of ASCVD utilizing a case-cohort study design. We will then examine whether addition of CEC to traditional risk factor scoring algorithms will improve the risk prediction of incident ASCVD in this population. Finally, we will determine whether different antiretroviral drugs are associated with lower or higher CEC by: a) comparing CEC between ALLRT participants receiving abacavir-containing versus tenofovir-containing, and protease inhibitors-containing versus non-nucleoside reverse transcriptase inhibitors- containing antiretroviral regimens; c) conducting in-vitro comparisons of CEC between sera from antiretroviral nave HIV-infected and non-HIV infected subjects exposed to various first-line antiretroviral drugs. ALLRT is a large cohort of HIV-infected patients that initiated ART as part of randomized clinical trials, with adjudicated cardiovascular events over long-term follow up, making it an ideal cohort for the proposed work. We have already measured the CEC and determined its association with incident ASCVD in the DHS. Taken together, results of this study could significantly advance understanding of the mechanisms of increased ASCVD risk associated with HIV and ART and refine ASCVD risk prediction in this high-risk population, results with immediate clinical implications. They could also form the basis for further research in mitigating that risk and establish a new basis for the evaluation of the ASCVD risk of current and future antiretroviral drugs.